Dabrafenib

Usage

• Dabrafenib is prescribed for the treatment of:

  • BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.
  • BRAF V600E mutation-positive non-small cell lung cancer (NSCLC).
  • BRAF V600E mutation-positive anaplastic thyroid cancer (ATC).
  • BRAF V600E mutation-positive unresectable or metastatic solid tumors in pediatric patients (≥1 year old) and low-grade glioma (LGG) who have progressed following prior treatment and have no satisfactory alternative treatment options.

• Pharmacological classification: Kinase inhibitor, specifically a BRAF inhibitor.

• Mechanism of Action: Dabrafenib selectively inhibits BRAF kinases, particularly the mutated BRAF V600E and V600K proteins found in certain cancers. These mutated proteins promote uncontrolled cell growth and division. By inhibiting these proteins, Dabrafenib helps slow or stop cancer growth.

Alternate Names

• INN: Dabrafenib

• Brand Name: Tafinlar

How It Works

• Pharmacodynamics: Dabrafenib targets the mutated BRAF V600E and V600K proteins, inhibiting their kinase activity and subsequently suppressing the MAPK signaling pathway. This pathway is crucial in regulating cell growth and survival, and its dysregulation due to BRAF mutations is implicated in the development and progression of various cancers.

• Pharmacokinetics:

  • Absorption: Oral bioavailability is approximately 95%, though delayed and reduced when taken with food (high-fat meals reduce absorption).
  • Metabolism: Primarily metabolized in the liver by CYP3A4 and CYP2C8 enzymes, resulting in active metabolites (hydroxy-dabrafenib, desmethyl-dabrafenib, carboxy-dabrafenib) with similar or greater exposure and BRAF inhibitory activity compared to the parent drug.
  • Elimination: Primarily eliminated through feces (71%), with a smaller portion excreted in urine (23%). The terminal half-life of Dabrafenib is approximately 8 hours, while its metabolites have longer half-lives (10-22 hours).

• Mode of Action: Dabrafenib acts as an ATP-competitive inhibitor, binding to the ATP-binding site of BRAF kinases and preventing ATP from binding. This blocks the kinase activity of BRAF, thereby disrupting the MAPK signaling cascade and halting downstream cellular processes that contribute to tumor growth.

• Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Dabrafenib primarily acts through enzyme inhibition, specifically by targeting BRAF kinases.

• Elimination pathways: Primarily hepatic metabolism via CYP3A4 and CYP2C8, followed by fecal elimination. Some renal excretion also occurs.

Dosage

Standard Dosage

Adults:

• 150 mg (two 75 mg capsules) twice daily, approximately 12 hours apart.
• Administered orally, at least one hour before or two hours after a meal.

Children (≥1 year old):

• Tablets for Oral Suspension:
  • 8-9 kg: 20 mg twice daily
  • 10-13 kg: 30 mg twice daily
  • 14-17 kg: 40 mg twice daily
  • 18-21 kg: 50 mg twice daily
  • 22-25 kg: 60 mg twice daily
  • 26-29 kg: 70 mg twice daily
  • 30-33 kg: 80 mg twice daily
  • 34-37 kg: 90 mg twice daily
  • 38-41 kg: 100 mg twice daily
  • 42-45 kg: 110 mg twice daily
  • 46-50 kg: 130 mg twice daily
  • ≥51 kg: 150 mg twice daily
• Capsules:
  • 26-37 kg: 75 mg twice daily
  • 38-50 kg: 100 mg twice daily
  • ≥51 kg: 150 mg twice daily

Special Cases:

• Elderly Patients: No initial dose adjustment is required, although closer monitoring for adverse events is advisable.
• Patients with Renal Impairment: Caution is recommended for severe renal impairment. No specific dose adjustment guidelines are available for moderate or severe renal impairment.
• Patients with Hepatic Dysfunction: No dose adjustment required for mild hepatic impairment. No clinical data are available for moderate to severe hepatic impairment; caution is recommended.
• Patients with Comorbid Conditions: Caution is required in patients with risk factors for QT prolongation, Torsades de pointes, diabetes, or autonomic neuropathy.

Clinical Use Cases

Dabrafenib is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in targeted cancer therapy based on confirmed BRAF V600 mutation status.

Dosage Adjustments

Dose reductions may be required for managing adverse reactions. Considerations for dose modification include renal or hepatic dysfunction, other comorbid conditions, and drug interactions.

Side Effects

Common Side Effects:

• Headache
• Fever (pyrexia)
• Joint, muscle, or back pain
• Nausea
• Diarrhea
• Constipation
• Loss of appetite
• Cough
• Runny nose
• Sore throat
• Hair loss
• Tiredness
• Dry or thickened skin
• Nail infections
• Numbness and tingling in extremities

Rare but Serious Side Effects:

• New or changing skin lesions (potential for new primary melanoma or cutaneous squamous cell carcinoma)
• Severe allergic reactions
• Eye problems (uveitis, iritis, vision changes)
• Heart problems (QT prolongation, arrhythmia)
• Severe bleeding
• Kidney or liver problems
• High blood sugar (hyperglycemia)
• Low blood cell counts (neutropenia, anemia, thrombocytopenia)
• Increased risk of infection

Long-Term Effects:

• Potential for secondary malignancies
• Chronic skin changes
• Cardiovascular complications

Adverse Drug Reactions (ADR):

• Any signs of severe allergic reaction (e.g., difficulty breathing, swelling)
• New skin lesions, changes in existing moles
• Signs of heart problems, eye problems, or bleeding
• Evidence of liver or kidney dysfunction
• Symptoms of infection

Contraindications

• Hypersensitivity to dabrafenib.
• Patients with wild-type BRAF melanoma, NSCLC or other cancers where BRAF V600 mutation is absent.

Drug Interactions

• CYP450 Interactions: Dabrafenib is metabolized by CYP3A4 and CYP2C8. Avoid potent CYP3A4 or CYP2C8 inhibitors or inducers.
• Other Drug Interactions: Dabrafenib may decrease the effectiveness of hormonal contraceptives. It can also interact with numerous other drugs, including anticoagulants, antiarrhythmics, certain antibiotics, and other kinase inhibitors. Refer to a comprehensive drug interaction database before co-prescribing.
• Food and lifestyle factors: High-fat meals reduce dabrafenib absorption.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (Australia); Not assigned (US FDA) - Known to cause fetal harm in animal studies; not recommended during pregnancy.
• Fetal Risks: Dabrafenib is teratogenic and embryotoxic in animal studies.
• Breastfeeding: Not recommended while breastfeeding and for 2 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: Selective BRAF kinase inhibitor, targeting V600E and V600K mutations.
• Side Effects: Common: fever, rash, fatigue, nausea, headache. Serious: new malignancies, eye problems, cardiac effects, bleeding.
• Contraindications: Hypersensitivity, wild-type BRAF tumors.
• Drug Interactions: Numerous drug interactions, including CYP3A4/2C8 inhibitors/inducers, hormonal contraceptives.
• Pregnancy & Breastfeeding: Contraindicated/Not recommended.
• Dosage: Adults: 150 mg BID. Pediatric dosing available.
• Monitoring Parameters: Monitor for skin changes, eye problems, cardiac effects, liver/kidney function, blood counts, and blood glucose levels.

Popular Combinations

• Trametinib: This MEK inhibitor is frequently combined with Dabrafenib for enhanced efficacy in BRAF-mutant melanoma and other cancers.

Precautions

• Confirm BRAF V600 mutation status before initiating treatment.
• Pre-screening for cardiac, liver, and kidney function is recommended.
• Dermatological evaluations should be performed regularly.
• Monitor for adverse events, especially those listed as rare but serious.
• Counsel patients on appropriate contraceptive methods.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dabrafenib?

A: Adults: 150 mg twice daily. Pediatric dosing is weight-based, and detailed information should be consulted.

Q2: How should Dabrafenib be taken?

A: Administer orally, at least one hour before or two hours after a meal. Swallow capsules whole; do not crush or open.

Q3: What are the most common side effects of Dabrafenib?

A: Fever, fatigue, nausea, headache, rash, joint pain, and hair loss.

Q4: What are the serious side effects to watch out for?

A: New or changing skin lesions, eye problems, cardiac effects, and signs of bleeding or infection.

Q5: Can Dabrafenib be used during pregnancy or breastfeeding?

A: Dabrafenib is not recommended during pregnancy and breastfeeding due to the potential risk of fetal harm and infant exposure.

Q6: What are the important drug interactions to be aware of?

A: Avoid co-administration with potent CYP3A4 and CYP2C8 inducers or inhibitors. Dabrafenib may also interact with hormonal contraceptives and various other medications.

Q7: What tests are necessary before starting Dabrafenib?

A: Confirmation of BRAF V600E or V600K mutation is essential before initiating treatment. Baseline cardiac, liver, and kidney function tests are also recommended.

Q8: What is the mechanism of action of Dabrafenib?

A: Dabrafenib is a selective inhibitor of BRAF kinases, targeting the V600E and V600K mutations that drive tumor growth in certain cancers.

Q9: What are the long-term potential effects of Dabrafenib?

A: Secondary malignancies and chronic skin changes are potential long-term effects. Regular monitoring is essential.

Q10: When should Dabrafenib treatment be discontinued?

A: Discontinue treatment upon disease progression or development of unacceptable toxicity.